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European Journal of Heart Failure 2006 8(5):532-538; doi:10.1016/j.ejheart.2006.04.004
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© 2006 European Society of Cardiology

NTproBNP-guided drug treatment for chronic heart failure: design and methods in the "BATTLESCARRED" trial

John G. Lainchbury, Richard W. Troughton, Christopher M. Frampton, Timothy G. Yandle, Amjad Hamid, M. Gary Nicholls and A. Mark Richards*

The Christchurch Cardioendocrine Research Group, Department of Medicine, The Christchurch School of Medicine and Health Sciences, University of Otago, and the Department of Cardiology Christchurch Hospital, Christchurch, New Zealand

* Corresponding author. Tel.: +64 3 364 1116; fax: +64 3 364 1115. E-mail address: barbara.griffin{at}chmeds.ac.nz


   Abstract
Top
 Abstract
1. Introduction
 2. Research design and...
 3. Discussion
 References
 
Background: How best to decide when to introduce drugs and what doses are optimal in individual patients with chronic heart failure (CHF), is unclear.

Aims: We will determine whether titration of drug treatment according to plasma NTproBNP is superior regarding clinical outcomes to intensive standardised clinical assessment; whether either of the regimens noted above is superior to usual care; and whether age alters the relative efficacy of NTproBNP guided treatment.

Methods: We will randomise 360 patients, stratified by age, to drug treatment directed by plasma NTproBNP, to intensive standardised clinical assessment, or to usual care. The primary outcome is total mortality, and secondary outcomes include death plus hospital admission for any cardiovascular event plus episodes of outpatient decompensated heart failure. Analyses will be conducted at the end of one and two years.

Results: 308 patients have been recruited, the majority being in NYHA functional class II, 60.6% being >75 years. The entry plasma NTproBNP level is 238, 50–1250 pmol/l, median and range, approximately 400–11,000 pg/ml.

Conclusion: sWe describe details of a study to test the potential utility of serial measurements of NTproBNP in adjusting the drug treatment of patients with CHF. Projected completion date is 2007.

Key Words: Chronic heart failure • BNP • NTproBNP • Drug therapy

Received December 12, 2005; Revised March 8, 2006; Accepted April 13, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Research design and...
 3. Discussion
 References
 
Patients with chronic heart failure (CHF) derive substantial benefits from treatment with angiotensin converting enzyme (ACE) inhibitors [1], angiotensin receptor blockers (ARBs) [2,3], beta-adrenergic blockers [4,5] and spironolactone [6]. Less clear is whether target doses of these drugs should be the same for all patients or should be decided on an individual basis. Individualisation may be rewarding in those with few limiting factors but less effective in others such as the elderly or those with reduced renal function who may require cautious drug titration. A tailored approach has obvious intuitive appeal but the uniform application of trial-based drug doses is the favoured approach embodied in current guidelines.

The efficacy of loop and thiazide diuretics is presumed rather than proven. Diuretic doses have traditionally been tailored to the individual based on a constellation of clinical and laboratory measures end-points, many of which are subjective, are liable to short-term variation and/or are affected by concurrent medications. It is unclear whether individualisation of diuretic doses based on an objective index of cardiac dysfunction would prove therapeutically superior to that provided by the above measures.

In view of these uncertainties we hypothesised that individualisation of drug therapy based on the degree of cardiac dysfunction would prove more effective than treatment dictated by a universal plan for all patients according to trial-based results and, in the case of loop or thiazide diuretics, based on a constellation of clinical and laboratory measures.

The obvious problem in testing this hypothesis has been the absence of a single reliable index of cardiac dysfunction. In that plasma levels of brain natriuretic peptide (BNP) and its N-terminal pro peptide, NTproBNP, offer a robust reflection of left ventricular function [7,8] and prognosis [9] together with the observation that drug-induced improvements in cardiac status are reflected by a fall in their circulating levels, commentators have suggested that natriuretic peptide levels might be used to optimise drug treatment.

To date, 2 studies have reported that treatment guided by natriuretic peptide levels provided protection against cardiovascular events compared to conventional, clinically guided therapy [10,11]. Follow-up periods were relatively short and these initial results require confirmation. Accordingly, we designed NTproBNP-AssisTed Treatment to LEssen Serial CARdiac REadmissions and Death ("BATTLESCARRED"), a randomised study, incorporating ‘usual care,’ intensive standardised clinical management and NTproBNP guided therapy groups, details of which are reported here.


   2. Research design and methods
Top
 Abstract
 1. Introduction
 2. Research design and...
3. Discussion
 References
 
2.1. Primary hypotheses
We have two major hypotheses. The first is that drug treatment aimed specifically at reducing plasma NTproBNP to <150 pmol/l (approximately 1300 pg/ml), will improve outcomes compared to treatment titration guided by intensive standardised clinical assessment. The second is that intensive follow-up of patients incorporating regular standardised clinical assessment, titration of medication according to NTproBNP level or a clinical score, along with patient education and regular follow-up will improve outcomes compared to patients receiving usual care. We further hypothesise that due to the potential problems associated with titrating treatments to target levels in the elderly, the effectiveness of NTproBNP guided therapy is influenced by age.

Additional secondary hypotheses relating to vasoactive hormones and cardiac tissue Doppler imaging, will not be addressed here.

2.2. Aims of the study

  1. To determine whether titration of drug treatment according to plasma NTproBNP is superior regarding clinical outcomes to that provided by intensive standardised clinical assessment.
  2. To determine whether intensive follow up by either of the two regimens noted above is superior regarding clinical outcomes versus usual care.
  3. To explore the effects of age on the relative efficacy of NTproBNP guided treatment.

2.3. Inclusion criteria
Patients >18 years with symptomatic CHF (as defined by Framingham criteria [12] and satisfying European Society of Cardiology (ESC) guidelines for the diagnosis of CHF [13]) requiring admission to hospital and able to give informed consent, will be enrolled. Immediate pre-randomisation plasma NTproBNP must exceed 50 pmol/l (i.e. approximately 400 pg/ml).

2.4. Exclusion criteria
Patients will be excluded if they have active myocarditis/pericarditis, life expectancy due to non-cardiovascular disease of <24 months, severe hepatic or pulmonary disease (FEV1<1 l), renal impairment (plasma creatinine >250 µmol/l), transient heart failure from myocardial infarction treated with acute revascularisation and a subsequent ejection fraction during the index hospital admission of >40%, severe valvular disease being considered for surgery, severe aortic stenosis (valve area <1 cm2), heart failure secondary to mitral stenosis or are under consideration for cardiac transplantation.

The aim is to recruit a broad range of patients including those with preserved left ventricular systolic function as well as those whose systolic function is impaired.

2.5. Research design
Patients will be recruited during admission to Christchurch Hospital with symptomatic CHF satisfying Framingham (two major and two minor criteria present concurrently) and ESC criteria [12,13]. Inpatient care will be undertaken according to the clinical practice of the admitting physician. Demographic and clinical data will be recorded, and pre-discharge echocardiography and plasma for NTproBNP obtained for immunoassay by our established method [14]. Qualifying patients will attend a randomisation outpatient visit within two weeks of discharge when they will be randomised, double blind, to one of three groups (Fig. 1):

  1. NTproBNP Guided Group
  2. Clinically Guided Group
  3. Usual Care Group


Figure 1
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  		Fig. 1 Outline of the study protocol for BATTLESCARRED. Gp=Group.

 
Usual Care patients will have no further contact with the research team other than a three monthly enquiry to document medications, adverse events, readmissions to hospital and death. Patients randomised to the NTproBNP and Clinically Guided groups will be seen at a minimum of three monthly intervals in the Christchurch Hospital research outpatient clinic. At each visit a full clinical assessment will be undertaken by a research study physician blinded to the patient's group assignment, clinical end points will be documented, and a venous sample drawn for NTproBNP and basic biochemistry. The plasma NTproBNP result will be available in the same week as the clinic visit for patients in the NTproBNP group and values in excess of the target (150 pmol/l) will trigger escalation of therapy supervised by an investigator other than the physician undertaking the clinical assessment.

Data will be recorded from pre-planned serial clinical history taking, physical examinations, echocardiography, 6-min walk tests and Minnesota Living With Heart Failure questionnaires.

Patient status at the time of clinical review will be recorded in the form of a "heart failure score" (Table 1) derived by assigning a value to a defined series of clinical variables based on Framingham data for a diagnosis of heart failure with major criteria each scoring 1 point and minor criteria each scoring 0.5 points. This score proved consistently applicable in the course of our earlier study where patients with scores <2 had minimal symptoms and were free from signs of CHF [10].


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  		Table 1 Heart failure score

 
2.6. Treatment
Patients in the NTproBNP and Clinically Guided groups will receive instructions on monitoring weight, salt restriction, resting after diuretic administration, exercise, avoidance of liquorice, NSAIDS and alcohol, and the need for influenza vaccination along with general education regarding CHF.

2.6.1. Clinically Guided group
The aim is to establish trial-based doses of therapies. At the initial clinic visit, the standardised clinical assessment will be undertaken and diuretics and ACE inhibitor doses, with or without digoxin, will be adjusted in order to stabilise the patient's condition ("heart failure score" <2). For patients with a score <2, trial-based doses of ACE inhibitors (enalapril 10 mg twice daily or equivalent) adjusted for renal function, will be prescribed. A beta-blocker will then be introduced or, for those already on a beta-blocker, the dose will be titrated at 2 weekly intervals towards trial-based doses of carvedilol (25 mg twice daily) or metoprolol CR (190 mg/day). Carvedilol is the preferred beta-blocker, but metoprolol, if already started, will be continued. After each adjustment of therapy, the patient will be seen for extra visits at 2 weekly intervals. If at any time a score ≥2 is recorded, this will be taken to suggest decompensation or inadequate treatment triggering intensification of therapy with adjustment of diuretic doses or addition of therapy including digoxin and spironolactone. The sequence is:

"Heart failure score"<2:

  1. Optimisation of ACE inhibitor dose.
  2. Addition and titration or optimisation of beta-blocker dose.

"Heart failure score" ≥2:

  1. Increase frusemide to 120 mg/day or optimisation of ACE inhibitor dose if suboptimal.
  2. Addition of digoxin 0.25 mg/day adjusted for creatinine clearance.
  3. Add spironolactone (up to 50 mg/day) in patients with persisting class III or IV symptoms.
  4. Increase frusemide with twice-daily doses up to a maximum of 500 mg twice daily with doubling increments.
  5. Addition of bendrofluazide or metolazone.

If at subsequent 2 week follow-up the "heart failure score" is <2, further titration of beta blockade may be undertaken.

If at any stage the assessing physician considers the patient requires hospital admission, this will be reviewed with another research physician blinded to the patient's group, and treatment including hospital admission undertaken as appropriate.

Intolerance of medication and inability to adjust doses further because of renal impairment, symptomatic hypotension or bradycardia must be taken into account such that the treatment algorithm will be individualised. However, the overall aim is to establish a stable clinical status with a "heart failure score" <2 and trial-based doses of ACE inhibitors and beta-blockers.

2.6.2. NTproBNP guided group
Drug treatment will be adjusted to achieve a plasma NTproBNP <150 pmol/l — a level seldom seen with a "heart failure score" ≥2 (10). At each visit, patients will be assessed as for the Clinically Guided Group, and a score ≥2 will similarly be taken to indicate decompensation requiring intensification of therapy as outlined above. Stable clinical status (score <2) but in the presence of a plasma NTproBNP >150 pmol/l will also trigger intensified treatment according to the following algorithm:

  1. Optimisation of ACE inhibitor to trial-based doses.
  2. Addition or titration of beta blockade to trial-based doses.
  3. Addition of further therapy as for the Clinically Guided Group.

Patients in either group requiring intensified therapy will be reviewed in approximately 2 weeks with clinical assessment and measurement of NTproBNP, plasma electrolytes and creatinine, plus checks for postural hypotension. Intolerance of medication will result in stepped withdrawal with preference given to initial reduction in diuretic doses.

Patients will be blinded as to their group allocation, and clinical assessments will be made by a physician also blinded. Intensification of drug treatment will be made by an unblinded physician in the research team. This approach was utilised successfully in our earlier study [10].

All patients in these two treatment limbs will remain in their designated group for 2 years after which they will attend routine cardiology outpatient clinics in Christchurch Hospital or their primary care physician. After the formal 2 year treatment period, the research team will make contact with each patient every 3 months as for the Usual Care Group to document clinical events, hospital admissions and death.

2.7. Outcomes
Analyses will be conducted on outcomes when all patients have finished a one year treatment period and again after 2 years, then at 3 and 5 years to determine carry-over effects. The primary outcomes include total mortality and the composite end-point of death plus episodes of inpatient or outpatient heart failure decompensation. Secondary outcomes include death plus hospital admission for any cardiovascular event (heart failure, acute coronary syndromes, stroke, TIA, peripheral vascular event, dysrrhythmia, or cardiac syncope) plus episodes of outpatient decompensated heart failure requiring increased medication. Third, any episode of heart failure decompensation. Fourth, total admissions. Additional secondary outcomes will include changes in NTproBNP, in NYHA status, in 6-min walk distance, in echocardiographic estimates of left ventricular systolic or diastolic function and in Minnesota heart failure questionnaire scores. The outcomes will be compared between the 3 arms of the study appropriate to the primary hypotheses. We postulate that there may be differential treatment group outcomes dependent upon age and therefore age grouping (≤ or >75 years) will be considered in the analyses.

2.7.1. Randomisation
Patients will be randomised to one of the three treatment arms in equal ratios, stratified by age (≤75 or >75 years) in permuted blocks of size 30.

2.7.2. Statistical analyses
The primary hypotheses will be tested on an intention-to-treat basis using Cox's proportional hazards regression models. These analyses will model the time to the first event relevant to the outcome measures described above. Included within these analyses will be the pertinent treatment arms, age and to test the mediating effects of age, the age by treatment arm interaction. Although confounding by baseline prognostic variables is unlikely in a randomised study of this size, the results of these analyses will be confirmed by inclusion of additional standard prognostic baseline measures including cardiovascular history, gender, diabetes, renal function, LVEF and NTproBNP levels in the proportional hazards models. The effects of treatment on total admissions will be tested using Poisson regression models following a similar strategy to the above survival analyses. A p-value <0.05 will be taken to indicate statistical significance.

2.7.3. Sample size and power analysis
Recruitment of patients was anticipated to occur over approximately five years so that if analyses were undertaken with a minimum of one year's follow-up this would provide a conservative estimate of median follow-up of three years. Existing data on this cohort of patients indicate a cumulative mortality of about 40% for usual care patients over this period. To show a relative risk reduction of 50% in either one of the other groups with 80% power using a two tailed P=0.05, would therefore, require 120 patients in each treatment arm. We therefore will recruit 360 patients over a period of approximately five years. Assuming that about 40% of enrolled patients will be <75 years old, analyses comparing the relative efficacies based on age groupings will have sufficient power (>80%) to detect relative risk reductions of 67% or greater.

2.8. Progress to date
As of October 2005, 308 patients have entered the study, the majority being in NYHA functional class 2 although all were in NYHA functional class IV at the time of their index admission which typically preceded the randomisation visit by 2-4 weeks. 61% of patients are >75 years (Table 2). The median NTproBNP level is well above the therapeutic target of 150 pmol/l, and 38.3% had a LVEF<40% (Table 2). The projected completion date for the 2-year formal follow-up is 2007. The mortality rate amongst 252 patients at one year is 30.2% and amongst 186 patients at 2 years, is 34.4%.


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  		Table 2 Admission and randomisation characteristics (n=308)

 

   3. Discussion
Top
 Abstract
 1. Introduction
 2. Research design and...
 3. Discussion
References
 
A major challenge is how best to manage the complex pharmacotherapy for CHF. Drugs in landmark studies [1-6] were added in a pre-determined fashion and increased in dosage according to a clear plan toward a set maximum. The outcomes, though salutary, leave open the question of whether the "cook book" approach, where one-size fits all regarding drug doses, is logical. Another issue not addressed is how best to determine the dose of loop (or thiazide) diuretics.

The alternative approach is to introduce and alter doses of medications according to an objective measure of cardiac function/dysfunction. A number of indices in this regard have been suggested. For example, plasma renin was proposed as a guide to ACE inhibitor treatment [15] but is unlikely to assist in deciding spironolactone, loop diuretic or beta-blocker doses. Plasma angiotensin II and aldosterone have also been proposed [16] but levels of the former increase with ARB therapy and its accurate determination is a challenge beyond routine laboratories, whilst the latter is unlikely to be useful since its levels rise with spironolactone treatment [17]. Continuous measurement of right ventricular hemodynamics using an implantable monitor has been utilized as a guide to day-to-day management [18], but is expensive and inconvenient.

Plasma levels of BNP (or NTproBNP) may prove useful in this regard. First, their circulating levels reflect left ventricular function [7,8]. Importantly, their levels decline as cardiac function improves with ACE inhibitor [19], ARB [20], loop diuretic [21] and spironolactone therapy [22]. Although the situation is complex with beta-blockers since natriuretic peptide levels may increase initially, they decline with sustained treatment in parallel with haemodynamic improvements [23-26]. Second, validated assays are widely available. Third, their measurement is convenient for patients and doctors. Fourth, results can be available within 15 min for point-of-care assays and in 60 min for automated assays. Finally, the cost of most assays is in the region of only US $20 per sample, and will decline with time.

Objective support for the use of natriuretic peptides in guiding therapy comes from two reports documenting a reduction in cardiovascular events in patients randomised to drug treatment guided by BNP or NTpro-BNP compared to standard care [10,11]. Furthermore, BNP has been considered potentially useful in the tailoring and monitoring of vasodilator [25] and beta-blocker [23] therapy in CHF.

Notwithstanding the outcomes of these studies, enthusiasm for the concept has varied from optimism [27] through caution [28] to unbridled antagonism [29]. The European Society of Cardiology states in a 2005 guideline update, "BNP and NTproBNP have considerable prognostic potential, although evaluation of their role in treatment monitoring remains to be determined" [30]. The 2005 guidelines on the diagnosis and management of CHF in the adult from the American College of Cardiology (ACC) and American Heart Association (AHA) state: "The use of BNP measurements to guide the titration of drug doses has not been shown to improve outcomes more effectively than achievement of the target doses of drugs shown in clinical trials to prolong life" [31]. Strictly, this statement is true since no trial has achieved target doses of all drugs for all patients. The ACC/AHA statement noted above is supported by reference to a single paper that points to the potential difficulties in using a single "cut-off" value as a target to guide therapy [32] — an issue addressed below. No reference to the two relevant studies [10,11] is made, regarding the question in hand. In any event, information from additional studies would be useful. Accordingly BATTLESCARRED was designed.

Whatever the outcome of BATTLESCARRED, the results may not apply to patients cared for under circumstances that differ from the trial. Since natriuretic peptide levels increase with age, are higher in women than men, tend to be lower in the obese and type II diabetics and are elevated as renal function declines, we speculate that the threshold for adding or increasing drug doses for CHF might need to be adjusted upward in the elderly, those with renal dysfunction and in women. In this regard it is possible that nomograms relating NTproBNP (and BNP) to age, glomerular filtration rate, gender, body mass index and diabetes will be useful in any systematic approach to pharmacotherapy guided by natriuretic peptide levels.

In that patients in BATTLESCARRED are being cared for in a specialist research clinic, those in the Clinically Guided Group are receiving intensive attention not typical of that provided under most other circumstances. Such intensive care in the Clinically Guided Group will tend to obscure any superiority of NTproBNP-guided therapy. Accordingly, we predict that any benefits resulting from NTproBNP-guided treatment in BATTLESCARRED will underestimate the benefits obtainable by the same approach under more usual clinical circumstances. Failure of NTproBNP-guidance to exhibit superiority over standard clinically guided care in BATTLESCARRED, therefore, must not be taken to suggest that this approach under other circumstances, especially in primary care, would not prove beneficial. Indeed, a formal trial along the lines of BATTLESCARRED in the primary care setting is required.


   Acknowledgements
 
We are grateful to the Health Research Council of New Zealand and the National Heart Foundation for financial support. The following are pivotal to the conduct of the study: Renee Malcolm, Kyla Tonkin, Kim Strangman, Barbara Griffin, Liz Campbell, Julia Osselton, Margaret Milne, Monica Johnston, Lorraine Skelton, Richard Hillock, Mark Davis, Steve Fisher, Niere Kitson and Reena John — to whom we are grateful.


   References
Top
 Abstract
 1. Introduction
 2. Research design and...
 3. Discussion
 References
 

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